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PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT

ABSTRACT: PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT

PROVIDER: PRJNA1117062 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29196564_1.fastq.gz	Fastqsanger.gz
	SRR29196564_2.fastq.gz	Fastqsanger.gz
	SRR29196565_1.fastq.gz	Fastqsanger.gz
	SRR29196565_2.fastq.gz	Fastqsanger.gz
	SRR29196566_1.fastq.gz	Fastqsanger.gz

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PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT

Project description:Chemoresistance is one of the major causes of poor prognosis in osteosarcoma. Thus far, the therapeutic alternative for osteosarcoma is quite limited, thereby increasing sensitivity of the currently used drugs is an effective way to improve outcome of patients. In this study, through a Kinome-wide CRISPR screen, we identified PRKDC as a critical determinant of Doxorubicin (DOX) sensitivity in osteosarcoma. Clinical sample analysis and functional experiments demonstrated that PRKDC is hyperactivated in osteosarcoma and that knockdown of PRKDC significantly increased sensitivity of osteosarcoma to DOX. Mechanistically, PRKDC could recruit and bind with GDE2 to augment the stability of GNAS. The increased GNAS protein subsequently activate Akt S473 and T308 phosphorylation and mediated DOX sensitivity. We also showed that the PRKDC inhibitor AZD7648 and DOX could synergize with each other and intensely suppressed the growth of osteosarcoma in mice xenograft models and human organoids. In conclusion, these results revealed a novel PRKDC-GDE2-GNAS-Akt regulatory axis in DOX sensitivity and provided targetable candidates for improving therapeutic efficacy of DOX in osteosarcoma.

2024-06-14 | GSE268415 | GEO

PRKDC Induces Chemoresistance in Osteosarcoma by Recruiting GDE2 to Stabilize GNAS and Activate AKT.

Project description:Chemoresistance is one of the major causes of poor prognosis in osteosarcoma. Alternative therapeutic strategies for osteosarcoma are limited, indicating that increasing sensitivity to currently used chemotherapies could be an effective approach to improve patient outcomes. Using a kinome-wide CRISPR screen, we identified PRKDC as a critical determinant of doxorubicin (DOX) sensitivity in osteosarcoma. The analysis of clinical samples demonstrated that PRKDC was hyperactivated in osteosarcoma, and functional experiments showed that the loss of PRKDC significantly increased sensitivity of osteosarcoma to DOX. Mechanistically, PRKDC recruited and bound GDE2 to enhance the stability of protein GNAS. The elevated GNAS protein levels subsequently activated AKT phosphorylation and conferred resistance to DOX. The PRKDC inhibitor AZD7648 and DOX synergized and strongly suppressed the growth of osteosarcoma in mouse xenograft models and human organoids. In conclusion, the PRKDC-GDE2-GNAS-AKT regulatory axis suppresses DOX sensitivity and comprises targetable candidates for improving the efficacy of chemotherapy in osteosarcoma. Significance: Targeting PRKDC suppresses AKT activation and increases sensitivity to doxorubicin in osteosarcoma, which provides a therapeutic strategy for overcoming chemoresistance.

| S-EPMC11372366 | biostudies-literature

Effect of Gnas knockout on mouse skin

Project description:Analysis of skin lesions from adult mice with epidermal conditional deletion of heterotrimeric G protein Galpha s in cytokeratin 14 positive cells, compared with control mouse skin. Epidermal Gnas ablation leads to skin defects, including basal cell carcinoma (BCC). Results provide insight into role of Galpha s in the regulation of stem cells from the skin. Changes in gene expression following Gnas deletion from the mouse epidermis were analyzed. Skin from four independent mice of each wild type (control) and Gnas epidermal knockout (Gnas eKO) were analyzed.

2014-06-28 | E-GEOD-58894 | biostudies-arrayexpress

Effect of mutant GNAS expression in the doxycycline-inducible Kras;Gnas mouse model of IPMN using scRNA-seq

Project description:We investigated the effect of GNAS(R201C) expression in the Kras;Gnas model of pancreatic intraductal papillary mucinous neoplasms where transgenic mutant GNAS is doxycycline inducible (LGKC; p48(Cre), Kras(LSL-G12D), Rosa26(LSL-rtTA)), Tg(TetO-GNAS(R201C)) using scRNA-seq of dissociated pancreatic tissues.

2024-09-15 | GSE275404 | GEO

GNAS-mosaicism

Project description:Parental mosaicism at GNAS gene

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Oncogene addiction to GNAS in GNASR201 mutant tumors

Project description:The GNASR201 gain-of-function mutation is the single most frequent cancer-causing mutation across all heterotrimeric G proteins, driving oncogenesis in various low-grade/benign gastrointestinal and pancreatic tumors. In this study, we investigated the role of GNAS and its product Gαs in tumor progression using peritoneal models of colorectal cancer (CRC). GNAS was knocked out in multiple CRC cell lines harboring GNASR201C/H mutations (KM12, SNU175, SKCO1), leading to decreased cell-growth in 2D and 3D organoid models. Nude mice were peritoneally injected with GNAS-knockout KM12 cells, leading to a decrease in tumor growth and drastically improved survival at 7 weeks. Supporting these findings, GNAS overexpression in LS174T cells led to increased cell-growth in 2D and 3D organoid models, and increased tumor growth in PDX mouse models. GNAS knockout decreased levels of cyclic AMP in KM12 cells, and molecular profiling identified phosphorylation of β-catenin and activation of its targets as critical downstream effects of mutant GNAS signaling. Supporting these findings, chemical inhibition of both PKA and β-catenin reduced growth of GNAS mutant organoids. Our findings demonstrate oncogene addiction to GNAS in peritoneal models of GNASR201C/H tumors, which signal through the cAMP/PKA and Wnt/β-catenin pathways. Thus, GNAS and its downstream mediators are promising therapeutic targets for GNAS mutant tumors.

2022-07-19 | GSE208278 | GEO

ATAC seq of Gnas mutant subcutaneous progenitor cells

Project description:The Gnas mutant mice driver by AdCre injection showed heterotopic osssification. In order to understand the underlying mechanism, we performed ATAC seq experiments from the control and Gnas mutant subcutaneous progenitor cells.

2020-11-23 | GSE161962 | GEO

RNA seq of Gnas mutant subcutaneous progenitor cells

Project description:The Gnas mutant mice driver by AdCre injection showed heterotopic osssification. In order to understand the underlying mechanism, we performed RNA seq experiments using total RNA from the control and Gnas mutant subcutaneous progenitor cells.

2020-11-21 | GSE161889 | GEO

Effect of mutant GNAS expression in doxycycline-inducible murine pancreatic cancer cell lines

Project description:We investigated the transcriptomic effect of GNAS(R201C) expression in murine cell lines derived from the Kras;Gnas model of pancreatic intraductal papillary mucinous neoplasms where transgenic mutant GNAS is doxycycline inducible (LGKC; p48(Cre), Kras(LSL-G12D), Rosa26(LSL-rtTA)), Tg(TetO-GNAS(R201C)) using bulk RNA-seq.

2024-09-15 | GSE275403 | GEO

Effect of GNAS mutation on the gene expression of HCT116 colon cancer cell line

Project description:To investigate the effect of activating GNAS mutation on gene expression of colorectal cancer cells, we utilized the GNAS R201C knockin cell line produced by Horizon Discovery Ltd. We compared the gene expression of parental and GNAS R201C/+ HCT116 cells with RNA-Seq, using four biological replicates.

2024-01-11 | GSE231943 | GEO

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